ABSTRACT ? Same as parent grant. Damage to myelin is a central feature in diseases such as multiple sclerosis (MS) and results in the disruption of the action potential, damage to the axon, and ultimately leads to degeneration. To date, there are no therapies for repair or remyelination in MS and this illustrates the greatest unmet need for patients living with MS. Functional screening for small molecules or biologicals that promote remyelination represents a major hurdle to the identification and development of rational therapeutics for MS. Recently we implemented a novel functional screen using fabricated micropillar arrays to identify compounds that greatly enhance oligodendrocyte remyelination (Mei et al., 2014). Many of the promising candidates identified activated or antagonized G-protein coupled receptor (GPCR) targets. In this proposal, we focus screening efforts on GPCR small molecule libraries to identify/confirm/validate receptor targets that either inhibit or promote myelination. We believe that GPCRs represent targetable receptors and pathways for the development of small molecule therapeutics for MS. In this proposal we will: 1. Perform high-throughput screening of GPCR small molecule libraries to identify agonists and antagonists that promote myelination. 2. Identify, confirm and validate novel receptors and pathways responsible for the regulation of oligodendrocyte differentiation and myelination. 3. Investigate the therapeutic implications of activating or blocking specific receptors during development and after demyelination. Our preliminary data identifies two specific GPCRs, one that inhibits (G ) and one that promotes (G /G ) differentiation and myelination of oligodendrocytes q io both during development and after demyelination.